The BTB domain transcription factors regulate the phenotype of normal and malignant cells by virtue of their repression of specific genetic programs. In particular two BTB proteins, Bcl-6 and PLZF play critical roles in non-Hodgkin? s lymphomas and retinoid resistant APL respectively. Both of these proteins repress target genes by interacting with co-repressors that recruit histone deacetylases. The BTB domain is required for transcriptional repression by these two proteins and thus represents the major functional motif of Bcl-6 and PLZF. We performed detailed structure-function studies on Bcl-6 and PLZF including crystallographic analysis of the BTB domains of both proteins, and found that a conserved charged pocket is the BTB docking site for co-repressors. Pocket mutants that abrogate co-repressor binding are unable to mediate transcriptional repression and are severely impaired for biological effects, demonstrating the central importance of the charged pocket for the entire proteins? functions. We also identified the reciprocal co-repressor consensus sequence that binds to the BTB pocket. Based on these findings, we hypothesize that the BTB domain charged pocket represents a potential target for development of specifically targeted transcriptional therapy agents that bind to the pocket motif. To validate the BTB pocket as a potential drug target, we intend to introduce the minimal pocket binding peptide into cells using protein transduction domains as carriers. Using this methodology we will determine the effect of these peptides in binding the BTB pocket in vivo, blocking co-repressor interaction in vivo, blocking transcriptional repression, and, most importantly, inhibiting the well characterized cell biological effects of PLZF and Bcl-6 as well as derepressing the target genes silenced by these proteins. In addition, we propose here to develop two high throughput screening assays which can be used in the future to identify compounds that occupy the BTB charged pocket and block co-repressor interactions. We expect this research to ultimately lead to the development of a new class of drugs which could provide targeted therapy of non-Hodgkin? s lymphomas as well as retinoid resistant acute promyelocytic leukemia.